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Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties¹

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

The heavy metal mercury elicits a genetically restricted autoantibody response in mice that targets the nucleolar autoantigen fibrillarin. HgCl₂-induced cell death of macrophages resulted in the proteolytic cleavage of fibrillarin. A prominent feature of mercury-induced cell death was the generation of a 19-kDa fragment of fibrillarin that was not found following apoptotic or nonapoptotic cell death induced by stimuli other than mercury. Proteolysis of fibrillarin lacking cysteines, and therefore unable to bind mercury, also produced the 19-kDa fragment, suggesting that a mercury-fibrillarin interaction was not necessary for the unique cleavage pattern of this self-Ag. In contrast to immunization with full-length fibrillarin, the 19-kDa fragment produced anti-fibrillarin Abs with some of the properties of the HgCl₂-induced anti-fibrillarin response. We propose that cell death following exposure to an autoimmunity-inducing xenobiotic can lead to the generation of novel protein fragments that may serve as sources of antigenic determinants for self-reactive T lymphocytes.